ReviewBisphosphonate effects on bone turnover, microdamage, and mechanical properties: What we think we know and what we know that we don't know
Introduction
The effect of bisphosphonates (BPs) to reduce bone remodeling has been appreciated since the early days of their discovery. Implicitly, reducing bone loss should result in reduced fracture risk. But suppression of remodeling alters material properties of bone and allows microdamage accumulation, changes that interact in complex ways to affect biomechanical integrity of the skeleton. Over the past 40 years, a number of reviews have detailed the effects of BPs on various tissue-level aspects of bone. The goal of this review is not to regurgitate what already can be found in these works but rather to briefly highlight key points regarding what is known about how BPs affect bone turnover, microdamage accumulation, and mechanical properties and then discuss where gaps in knowledge exist in each of these areas. We hope outlining some of these knowledge gaps will continue to stimulate work on BPs with the goal of optimizing BP treatment, and skeletal health in general, in the years to come.
Section snippets
BPs and bone turnover — what we know (Table 1)
In the adult skeleton, the majority of osteoblast and osteoclast activity involves coupled remodeling in which the process of bone resorption and formation are linked in space and time. The negative bone balance associated with each remodeling unit (more bone is resorbed than is formed) combined with the accelerated number of remodeling units both contribute to bone loss in postmenopausal osteoporosis. To a lesser extent the adult skeleton also undergoes modeling — where either formation or
BPs and bone turnover — what we don't know (Table 1)
With the goal of reducing fracture risk to the greatest degree, the push within the field has generally been to reduce bone turnover to the greatest degree possible. Yet it remains unclear whether the basic premise of more turnover suppression equals greater fracture risk reduction is correct. In fact, it seems rather clear that it is not. Raloxifene, a selective estrogen receptor modulator, suppresses bone remodeling by only 20–40%, yet achieves nearly the same fracture risk reduction in the
BPs and microdamage — what we know (Table 2)
It is now well established in animal models that the suppression of remodeling allows microdamage accumulation [36], [50], [51], [52], and that this is not necessarily a BP-specific effect [53]. Any suppression of remodeling will prevent the repair of naturally occurring damage to bone, and will allow it to accumulate. Even a 40% suppression of remodeling with a half-dose of risedronate caused a 3-fold increase in microdamage accumulation [54], and a 20% suppression with a non-BP, raloxifene,
BPs and microdamage — what we don't know (Table 2)
It is still an unresolved question whether microdamage accumulates in postmenopausal women who have taken BPs. Stepan et al. [67], using human transilial biopsies, showed in a subsample that microcrack accumulation occurs in women treated for an average of 5 years with alendronate, but the study is inconclusive because the analysis of biopsies from the two different research centers associated with the study differed. However, Stepan et al. were able to show definitively that microcrack
BPs and biomechanical properties — what we know (Table 4)
The efficacy of BPs on reducing fracture risk is clear and relatively consistent [1], [77]. New vertebral fractures are significantly reduced over three years with alendronate, risedronate, ibandronate, and zoledronate relative to placebo-treated controls. Non-vertebral fracture risk reduction is also significantly lower with all four BPs over the first three years. When hip fractures are assessed independent of other non-vertebral sites, only alendronate, risedronate, and zoledronate show
BPs and biomechanical properties — what we don't know (Table 4)
In life, bone is loaded cyclically and not quasi-statically, and the properties of the bone in cyclic loading, and its residual fatigue life with additional cycles of loading, may not be estimated very accurately from quasi-static tests of structural or material biomechanical properties. Cyclic fatigue tests of bone treated with BPs have not been performed to determine whether the reduced toughness measured quasi-statically translates into reduced residual strength and shorter fatigue life of
Summary
The BPs have been extremely successful in reducing fracture risk and improving patients' quality of life. Still, given how much attention has been paid to these agents, there is still much to learn. Much of this has less to do with the drugs themselves, than with the role that remodeling suppression plays in bone physiology and maintenance. For example, while we know that suppressing bone turnover is important to prevent fractures in postmenopausal women, we don't know how suppression is
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